Pyrazole compounds

ABSTRACT

Compounds of the formula (I) and salts and solvates thereof, in which X, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  have the meanings indicated in Claim  1 , are suitable as ligands of 5 HT receptors.

The invention relates to compounds of the formula I

in which

-   R², R⁴ denote H, A, Hal, cycloalkyl having 3 to 7 C atoms, CF₃, NO₂,    CN, OCF₃, OA, NHA, NA₂, NH₂,-   R³, R⁶ denote (CH₂)_(n)Het, (CH₂)_(n)Ar,-   R¹ denotes H or an organic radical, in particular (CH₂)_(n)CO₂R⁵,    (CH₂)_(n)COHet, CHO, (CH₂)_(n)OR⁵, (CH₂)_(n)Het, (CH₂)_(n)N(R⁵)₂,    CH═N-OA, CH₂CH═NOA, (CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het,    (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OR⁵,    (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁵)C(R⁵)COOR⁵,    (CH₂)_(n)N(R⁵)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,    (CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)CH₂COOR⁵,    (CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het,    CH═CHCH₂N(R⁵)₂, CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar,-   R⁵ denotes H or A-   A denotes straight-chain or branched alkyl or alkoxy having 1 to 10    C atoms, alkenyl or alkenyloxyalkyl having 2 to 10 C atoms,-   Het denotes an organic radical, in particular a saturated,    unsaturated or aromatic mono- or bicyclic heterocyclic or linear or    branched organic radical containing one or more hetero atoms which    is unsubstituted or mono- or polysubstituted by A and/or Hal,-   Ar denotes an organic aromatic radical, in particular a phenyl    radical which is unsubstituted or mono- or polysubstituted by A    and/or Hal, OR⁵, OOCR⁵, COOR⁵, CON(R⁵)₂, CN, NO₂, NH₂, NHCOR⁵, CF₃,    SO₂CH₃ or a ring-forming group —OCH₂O—, —O(CH₂)₂O— or —OC(CH₃)₂O—,-   n denotes 0, 1, 2, 3, 4 or 5-   and-   Hal denotes F, Cl, Br or I    where, in the case that X has the meaning CH, R² and R⁴ do not    simultaneously denote H,    and salts and solvates, enantiomers, racemates thereof and other    mixtures of the enantiomers, in particular physiologically tolerated    salts and solvates thereof.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and salts andsolvates thereof have very valuable pharmacological properties and arewell tolerated.

The invention relates, in particular, to the compounds mentioned in theexamples, which have the properties and potential uses of the compoundsof the formula I that are outlined in the present application.

In particular, the compounds of the formula I according to the inventionare suitable as ligands of 5 HT receptors, and consequently thecompounds according to the invention, and salts and solvates,enantiomers and racemates thereof, in particular physiologicallytolerated salts and solvates thereof, are suitable for the treatment andprophylaxis of diseases which can be influenced by the binding of thecompounds of the formula I to 5 HT receptors.

Similar compounds are disclosed, for example, in DE 2201889, DE 2258033or DE 2906252.

In particular, the compounds of the formula I according to the inventionare suitable as ligands of 5 HT2A and/or 5HT2C receptors and can be usedin human and veterinary medicine for the prophylaxis and treatment ofvarious diseases of the central nervous system, such as, for example,schizophrenia, depression, dementia, dyskinesia, Parkinson's disease,Alzheimer's disease, Lewy bodies dementia, Huntington's, Tourette'ssyndrome, anxiety, learning and memory impairments, neurodegenerativediseases and other cognitive impairments, as well as nicotine dependenceand pain.

The compounds of the formula I and/or physiologically acceptable saltsor solvates thereof are particularly preferably used for the preparationof a medicament for the prophylaxis and/or treatment of psychoses,neurological disorders, amyotrophic lateral sclerosis, eating disorders,such as bulimia, anorexia nervosa, of premenstrual syndrome and/or forpositively influencing obsessive-compulsive disorder (OCD).

It has been found that the compounds of the formula I andphysiologically acceptable salts and solvates thereof, while being welltolerated, have valuable pharmacological properties since they haveactions on the central nervous system. The compounds have strongaffinity to 5-HT_(2A) receptors, they furthermore exhibit 5-HT_(2A)receptor-antagonistic properties.

Preference is therefore given to the use of the compounds of the formulaI and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament having a 5-HT receptor-antagonistic action,in particular a 5-HT_(2A) receptor-antagonistic action.

For in-vitro detection of the affinity to 5-HT_(2A) receptors, thefollowing test (Example A1), for example, can be used. The 5-HT_(2A)receptors are exposed both to [³H]ketanserine (a substance known for itsaffinity to the receptor) and also to the test compound. The decrease inthe affinity of [³H]ketanserine to the receptor is an indication of theaffinity of the test substance to the 5-HT_(2A) receptor. The detectionis carried out analogously to the description by J. E. Leysen et al.,Molecular Pharmacology, 1982, 21: 301-314, or as also described, forexample, in EP 0320983.

The efficacy of the compounds according to the invention as 5-HT_(2A)receptor antagonists can be measured in vitro analogously to W. Feniuket al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in:The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard J R, OxfordUniversity Press, New York, 1989, p. 110. Thus, the contractility of therat tail artery caused by 5-hydroxytryptamine is mediated by 5-HT_(2A)receptors. For the test system, vessel rings prepared from the ventralrat tail artery are subjected to perfusion in an organ bath containingan oxygen-saturated solution. By introducing increasing concentrationsof 5-hydroxytryptamine into the solution, a response is obtained to thecumulative concentration of 5-HT. The test compound is then added to theorgan bath in suitable concentrations, and a second concentration curvefor 5-HT is measured. The strength of the test compound in shifting the5-HT-induced concentration curve to higher 5-HT concentrations is ameasure of the 5-HT_(2A) receptor-antagonistic property in vitro.

The 5-HT_(2A)-antagonistic property can be determined in vivoanalogously to M. D. Serdar et al., Psychopharmacology, 1996, 128:198-205.

The compounds of the formula I are therefore suitable both in veterinaryand in human medicine for the treatment of functional disorders of thecentral nervous system and of inflammation. They can be used for theprophylaxis of and for combating the consequences of cerebral infarctionphenomena (apoplexia cerebri), such as strokes and cerebral ischaemia,and for the treatment of extrapyramidal motor side effects ofneuroleptics and of Parkinson's disease, for the acute and symptomatictherapy of Alzheimer's disease and for the treatment of amyotrophiclateral sclerosis. They are likewise suitable as therapeutic agents forthe treatment of brain and spinal cord traumas. In particular, however,they are suitable as medicament active ingredients for anxiolytics,antidepressants, antipsychotics, neuroleptics, antihypertonics and/orfor positively influencing obsessive-compulsive disorder (OCD; forexample WO 9524194), anxiety states and physiological changes associatedwith anxiety states, such as, for example, tachycardia, tremor orsweating (for example EP 319962), panic attacks, psychoses,schizophrenia, anorexia, delusional obsessions, agoraphobia, migraine,Alzheimer's disease, sleep disorders, including sleep apnoea, tardivedyskinesia, learning disorders, age-dependent memory disorders, eatingdisorders, such as bulimia, drugs misuse, such as, for example, ofalcohol, opiates, nicotine, psychostimulants, such as, for example,cocaine or amphetamines (for example U.S. Pat. No. 6,004,980), sexualdysfunctions, conditions of pain of all types and fibromyalgia (forexample WO 9946245). The compounds of the formula I are suitable for thetreatment of extrapyramidal side effects (EPS) in neuroleptic drugtherapy. EPS is characterised by Parkinson's-like syndromes, acathisiaand dystonic reactions (for example EP 337136). They are furthermoresuitable for the treatment of anorexia nervosa, angina, Reynaud's,coronary vasospasms, in the prophylaxis of migraine (for example EP208235), pain and neuralgia (for example EP 320983), for the treatmentof Rett syndrome with autistic traits, of Asperger's syndrome, of autismand autistic disorders, in concentration deficit states, developmentaldisorders, hyperactivity states with mental underdevelopment andstereotypical behaviour states (for example WO 9524194).

They are furthermore suitable for the treatment of endocrine diseases,such as hyperprolactinaemia, furthermore in vasospasms, thromboticdiseases (for example WO 9946245), hypertension and gastrointestinaldiseases.

They are furthermore suitable for the treatment of cardiovasculardiseases and extrapyramidal symptoms, as described in WO 99/11641 onpage 2, line 24-30.

The compounds according to the invention are furthermore suitable forreducing the intraocular pressure and for the treatment of glaucoma.They are also suitable for the prophylaxis and treatment of poisoningphenomena on administration of ergovaline to animals.

The compounds are furthermore suitable for the treatment of diseases ofthe cardiovascular system (WO 99/11641, page 3, line 14-15). Thecompounds according to the invention can also be employed together withother active ingredients in the treatment of schizophrenia. Suitableother active ingredients are the compounds mentioned in WO 99/11641 onpage 13, line 20-26.

Other compounds which likewise exhibit 5-HT₂-antagonistic actions aredescribed, for example, in EP 0320983.

WO 99/11641 describes phenylindole derivatives having 5-HT₂-antagonisticproperties.

However, none of the above-mentioned documents describes the compoundsof the formula I according to the invention or the use thereof asligands of 5 HT receptors.

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine. They can furthermore beemployed as intermediates for the preparation of further medicamentactive ingredients.

The invention accordingly relates to the compounds of the formula I andto the use thereof in human and animal medicine.

The present invention furthermore relates to a process for thepreparation of compounds of the formula IA

and salts and solvates thereof, which is characterised in that acompound of the formula II

or acid-addition salts thereofin whichR⁴, R⁶ and X have the meanings indicated above,is reacted with a compound of the formula III

in whichA and R³ have the meanings indicated above,and/or in that a basic compound of the formula IA is converted into oneof its salts by treatment with an acid.

The present invention furthermore relates to a process for thepreparation of compounds of the formula IB

and salts and solvates thereof, which is characterised in that acompound of the formula II

or acid-addition salts thereofin whichR⁴, R⁶ and X have the meanings indicated above,is reacted with a compound of the formula IV

in whichA and R³ have the meanings indicated above,and/or in that a basic compound of the formula IB is converted into oneof its salts by treatment with an acid.

The compounds of the formulae IA and IB can be converted into thefurther compounds of the formula I by conventional methods. Inparticular, the compounds of the formula IA and IB can be converted,using reducing agents, such as, for example, lithium aluminium hydride,into the corresponding alcohols of the formulae IC and ID

which can be oxidised, for example using MnO₂, to the compounds IE andIF.

The compounds of the formulae IE and IF can themselves be aminated byknown processes using corresponding nucleophiles, such as, for example,nitrogen bases, in particular hydroxylamine, O-methylhydroxylamine,morpholine, piperidine, piperazine, N-methylpiperazine,4-methylpiperazin-1-ylamine, pyrrolidine, pyrazolidine or imidazolidine,optionally in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, or converted into the corresponding imines.Furthermore, the compounds of the formulae IE and IF can be converted,by Wittig reaction with methoxymethyltriphenylphosphonium salts, intothe corresponding enol ethers, which can be converted into thehomologised aldehydes IG and H

by treatment with an acid. The compounds of the formula IG and IH can beconverted into the further compounds of the formula I analogously to thecompounds of the formulae IE and IF.

The invention likewise relates to the novel compounds of the formula II,III, IV and V.

Solvates of the compounds of the formula I are taken to mean adductionsof inert solvent molecules onto the compounds of the formula I whichform owing to their mutual attractive force. Solvates are, for example,mono- or dihydrates or alcoholates.

Above and below, the radicals X, A, Ar, Het, n, R¹, R², R³, R⁴, R⁵ andR⁶ have the meanings indicated for the formula I, unless expresslystated otherwise.

X preferably denotes N.

R⁶ preferably stands for (CH₂)_(n)Ar, in particular for Ar. R⁵ veryparticularly preferably denotes phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- orn-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro-,dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxy- ortriethoxyphenyl, thiophen-2-yl or thiophen-3-yl.

R³ preferably denotes (CH₂)_(n)Het or (CH₂)_(n)Ar, in particular(CH₂)_(n)Ar. R³ very particularly preferably denotes phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-,n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-difluoro- ordicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-,4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolinyl, 2-or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl or 2- or3-furanyl.

If R¹ denotes H, R² preferably has the meaning Hal, CN or alkyl having 1to 7 C atoms, but in particular methyl, ethyl. If R² denotes H, R¹preferably has the meaning (CH₂)_(n)CO₂R⁵, (CH₂)_(n)CO-Het, CHO, CH₂OR⁵,(CH₂)_(n)-Het, (CH₂)_(n)N(R⁵)₂ or CH═N—OA, but in particular(CH₂)_(n)CO₂R⁵, (CH₂)_(n)CO-Het, CHO, CH═N—OA or (CH₂)_(n)-Het. R²particularly preferably denotes H.

Further preferred meanings of R¹ and R² arise from the examples.

R⁴ preferably denotes H, Hal, CN, A or NO₂, in particular H or Hal.

R⁵ preferably has the meaning A.

R⁶ preferably denotes (CH₂)_(n)Ar, in particular Ar.

A preferably denotes alkyl, is preferably unbranched and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms, preferably 1, 2, 3, 4, 5 or 6 C atoms, andpreferably denotes methyl, ethyl, n- or propyl, furthermore preferablyisopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl,neopentyl, isopentyl or n-hexyl. Particular preference is given tomethyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl orn-decyl.

A furthermore preferably has the meaning of the (CH₂)_(m)OCH₃ or(CH₂)_(m)C₂H₅ group, in which m denotes 2, 3, 4, 5 or 6, but inparticular 2.

If A denotes alkenyl, it preferably stands for alkyl, 2- or 3-butenyl,isobutenyl, sec-butenyl, furthermore preferably 4-pentenyl, isopentenylor 5-hexenyl.

Het is preferably an aromatic and in particular saturated heterocyclicradical which is unsubstituted or substituted by A. Het preferablydenotes 1-piperidyl, 1-piperazyl, 1-(4-methyl)piperazyl,1-(4-ethyl)piperazinyl, 1-(4-cyclopentyl)piperazinyl,4-methylpiperazin-1-ylamine, 1-pyrrolidinyl, 1-pyrazolidinyl1-(2-methyl)pyrazolidinyl, 1-imidazolidinyl or1-(3-methyl)imidazolidinyl or 4-pyridyl, which may be unsubstituted orsubstituted by one or more CN group, 2- or 4-pyridazyl, 2-, 4- or5-pyrimidyl, 2- or 3-pyrazinyl. Het furthermore preferably denotes aradical from the following table:

Het particularly preferably denotes one of the following radicals:

Ar preferably denotes a phenyl radical which is unsubstituted orsubstituted by Hal, OH, CN, NO₂, NH₂, NHCOCH₃, COOCH₃, CONH₂ or CF₃. Aris preferably substituted in the 4- or 3-position.

n preferably denotes 0, 1 or 2, in particular 0 or 1.

Cycloalkyl preferably has 3-7 C atoms and preferably stands forcyclopropyl and cyclobutyl, furthermore preferably for cyclopentyl orcyclohexyl, furthermore also for cycloheptyl, particularly preferablycyclopentyl.

Hal preferably denotes F, Cl or Br, but also I.

If the compounds of the formula I has one or more chiral C atoms, thepresent invention relates to the enantiomers, diastereomers and mixturesthereof.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The compound of the formula III is preferably obtained by reaction ofcompounds of the formula V

in which A has the meaning indicated above,with compounds of the formula VI

in which R³ and A have the meaning indicated above,under conditions known for such reactions.

The starting materials can, if desired, also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

On the other hand, it is possible to carry out the reaction stepwise.

The starting materials of the formulae II, III and IV are generallyknown. If they are not known, they can be prepared by methods known perse.

Specifically, the reactions of the compounds of the formula II with thecompounds of the formula III and the compounds of the formula IV arecarried out in the presence or absence of a preferably inert solvent attemperatures between about −20 and about 150°, preferably between 20 and100°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethaneor nitrobenzene; esters, such as ethyl acetate, or mixtures of the saidsolvents.

The pH necessary for the reaction can be set in accordance with pHvalues selected for similar reactions of carbonyl compounds with aminocompounds. The pH is preferably pre-specified through the use of theparticular acid-addition salt, preferably a hydrogen halide additionsalt, of the compound of the formula II, i.e. there is no additionaladdition of a base or acid to the reaction mixture. Preferredacid-addition salts are hydrochlorides or hydrobromides

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,laurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

On the other hand, if desired, the free bases of the formula I can beliberated from their salts using bases (for example sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate).

The invention relates, in particular, to compounds of the formula I andphysiologically acceptable salts and solvates thereof as medicaments.

The invention also relates to the compounds of the formula I andphysiologically acceptable salts and solvates thereof as glycinetransporter inhibitors.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts and/or solvatesthereof for the preparation of pharmaceutical compositions, inparticular by non-chemical methods. In this case, they can be convertedinto a suitable dosage form together with at least one solid, liquidand/or semi-liquid excipient or adjuvant and, if desired, in combinationwith one or more further active ingredients.

The invention furthermore relates to pharmaceutical compositionscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts and/or solvates.

These compositions can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc, Vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The compositionsindicated may be sterilised and/or comprise adjuvants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, dyes, flavours and/or one or more further activeingredients, for example one or more vitamins.

In general, the substances according to the invention are preferablyadministered here in doses of between 1 and 500 mg, in particularbetween 5 and 100 mg, per dosage unit. The daily dose is preferablybetween about 0.02 and 10 mg/kg of body weight. However, the specificdose for each patient depends on a very wide variety of factors, forexample on the efficacy of the specific compound employed, on the age,body weight, general state of health, sex, on the diet, on the time andmethod of administration, on the excretion rate, medicament combinationand severity of the particular disease to which the therapy applies.Oral administration is preferred.

Preferred compounds of the formula I have nanomolar affinity to the 5HT_(2A) receptors. Particularly preferred compounds of the formula Ihave low affinity to the 5 HT2C receptor. Very particularly preferredcompounds of the formula I exhibit no significant glycine transporteractivity.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, themixture is extracted with ethyl acetate or dichloromethane, the phasesare separated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation.

EXAMPLE 1

130 g of monoethyl malonate potassium salt are suspended in 2 l of ethylacetate in a 6 l three-necked flask provided with stirrer, condenser,thermometer, dropping funnel and drying tube, 127 ml of triethylamineand 82.4 g of magnesium chloride (anhydrous) are added with cooling andstirring at 0° C., and the mixture is slowly warmed to 35-40° C.Stirring is continued at this temperature for 6 h, the mixture is againcooled to 0° C., and a solution of 50 ml of furan-2-carbonyl chloride in1 l of ethyl acetate is added dropwise over the course of 15 minuteswith cooling and stirring at 0° C. Stirring is continued overnight atRT, then 1.2 l of 13% hydrochloric acid are added dropwise with coolingand stirring, and the ethyl acetate phase is separated off. Conventionalwork-up gives the product 2 as slightly yellowish liquid. (b.p. 85°C./0.6-0.5 mbar).

EXAMPLE 2

5 g of ethyl 2-furoylacetate are dissolved in 100 ml of THF, abs., in a250 ml flask provided with magnetic stirrer, condenser and drying tube,7.4 ml of N,N-dimethylformamide dimethyl acetal are added, and themixture is stirred under reflux for 6 h. The reaction solution was thenstripped off to give the residue 6.38 g (100%), giving 3.

EXAMPLE 3

4.49 g of the beta-keto ester 3 are dissolved in 90 ml of abs. ethanolin a 250 ml one-necked flask provided with magnetic stirrer, condenserand drying tube, 4.2 g of 4-bromophenylhydrazinium chloride are added,and the mixture is stirred under reflux overnight. Conventional work-upgives 4.

EXAMPLE 4

2.00 g of the aryl bromide 4 and 0.203 g of[1,1′-bis(diphenylphosphino)-ferocene)palladium(II) dichloride aredissolved successively in 80 ml of dimethoxyethane, 1.40 g of4-fluorophenylboronic acid are added, and a solution of Na₂CO₃ in water(5.87 g in 25 ml) is subsequently added. The reaction solution isstirred overnight at RT. For work-up, the reaction batch is partitionedbetween diethyl ether and water. Conventional work-up gives 5.

EXAMPLE 5

1.60 g of the ester 5 are initially introduced in THF, cooled to about 5to 0° C., and 4.3 ml of a 1 M solution of LiAlH₄ in THF is subsequentlyslowly added dropwise. When the addition is complete, stirring iscontinued overnight at room temperature. Conventional work-up gives 6crystalline solid.

EXAMPLE 6

1.4 g of the alcohol 6 is dissolved in a mixture of 10 ml of THF and 40ml of dichloromethane. 2.62 g of manganese dioxide are subsequentlyadded, and the reaction batch is stirred overnight at RT. Conventionalwork-up gives the product 7 as crystalline solid.

EXAMPLE 7

36 μl of CH₃COOH are added to a mixture of 200 mg of the aldehyde 7, 103mg of ethylpiperazine, 3.6 ml of 1,2-dichloroethane and 1.8 ml of THF.The mixture is stirred at room temperature for 3 h. 0.23 g of NaB(OAc)₃Hare subsequently added, and stirring is continued for 16 h.

Conventional work-up gives1-ethyl-4-[1-(4′-fluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]piperazinedihydrochloride 8 as colourless solid.

The following compounds of the formula I are obtained analogously usingthe corresponding precursors:

EXAMPLES 8-51

-   (8)    1-[1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (9)    1-[1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-ethylpiperazine-   (10)    1-[1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (11)    1-[1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]piperazine-   (12)    [1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]dimethylamine-   (13)    [1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]ethylmethylamine-   (14)    [1-(3,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]methyl-(1-methylpyrrolidin-3-yl)amine-   (15)    1-[1-(2,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (16)    [1-(2,4′-Difluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]ethylmethylamine-   (17)    1-[1-(4′-Fluorobiphenyl-4-yl)-3-methyl-5-phenyl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (18)    Ethyl-[1-(4′-fluorobiphenyl-4-yl)-3-methyl-5-phenyl-1H-pyrazol-4-ylmethyl]methylamine-   (19) (1-Biphenyl-4-yl-3-methyl-5-phenyl-1H-pyrazol-4-yl)acetic acid    ethyl ester-   (20) 2-(1-Biphenyl-4-yl-3-methyl-5-phenyl-1H-pyrazol-4-yl)ethanol-   (21)    1-{5-[2-(4′-Fluorobiphenyl-4-yl)-5-methyl-2H-pyrazol-3-yl]furan-2-ylmethyl}-4-methylpiperazine-   (22)    1-Ethyl-4-{5-[2-(4′-fluorobiphenyl-4-yl)-5-methyl-2H-pyrazol-3-yl]-furan-2-ylmethyl}piperazine-   (23)    Ethyl-{5-[2-(4′-fluorobiphenyl-4-yl)-5-methyl-2H-pyrazol-3-yl]furan-2-ylmethyl}methylamine-   (24)    1-{5-[2-(4′-Fluorobiphenyl-4-yl)-5-methyl-2H-pyrazol-3-yl]furan-2-ylmethyl}pyrrolidin-3-ol-   (25)    1-[1-(4′-Fluorobiphenyl-4-yl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (26)    1-Ethyl-4-[1-(4′-fluorobiphenyl-4-yl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]piperazine-   (27)    Ethyl-[1-(4′-fluorobiphenyl-4-yl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]methylamine-   (28)    1-[1-(4′-Fluorobiphenyl-4-yl)-5-methyl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (29)    1-Ethyl-4-[1-(4′-fluorobiphenyl-4-yl)-5-methyl-1H-pyrazol-4-ylmethyl]piperazine-   (30)    1-[1-(4′-Fluorobiphenyl-4-yl)-5-methyl-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (31)    Ethyl-[1-(4′-fluorobiphenyl-4-yl)-5-methyl-1H-pyrazol-4-ylmethyl]-methylamine-   (32)    1-[1-(4′-Fluorobiphenyl-4-yl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-pyrrolidin-3-ol-   (33)    1-[1-(4′-Fluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (34)    1-[1-(4′-Fluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (35)    1-Ethyl-4-[1-(4′-fluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]-piperazine-   (36)    1-[1-(4′-Fluoro-2-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (37)    1-Ethyl-4-[1-(4′-fluoro-2-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]piperazine-   (38)    Ethyl-[1-(4′-fluoro-2-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]methylamine-   (39)    1-[1-(4′-Fluoro-2-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (40)    1-[1-(2-Chloro-4′-fluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (41)    1-[1-(2-Chloro-4′-fluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-ethylpiperazine-   (42)    1-[1-(2-Chloro-4′-fluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (43)    [1-(2-Chloro-4′-fluorobiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]ethylmethylamine-   (44)    1-[1-(4′-Fluoro-3-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (45)    1-Ethyl-4-[1-(4′-fluoro-3-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]piperazine-   (46)    1-[1-(4′-Fluoro-3-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (47)    Ethyl-[1-(4′-fluoro-3-methylbiphenyl-4-yl)-5-furan-2-yl-1H-pyrazol-4-ylmethyl]methylamine-   (48)    1-[5-Furan-2-yl-1-(2,6,4′-trifluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]-4-methylpiperazine-   (49)    1-Ethyl-4-[5-furan-2-yl-1-(2,6,4′-trifluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]piperazine-   (50)    1-[5-Furan-2-yl-1-(2,6,4′-trifluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]pyrrolidin-3-ol-   (51)    Ethyl-[5-furan-2-yl-1-(2,6,4′-trifluorobiphenyl-4-yl)-1H-pyrazol-4-ylmethyl]methylamine

The examples below relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced in aconventional manner into hard gelatine capsules in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation Spray

14 g of active ingredient of the formula I are dissolved in 10 l ofisotonic NaCl solution, and the solution is transferred intocommercially available spray containers with pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1. A compound of formula I

in which R², R⁴ denote H, A, Hal, cycloalkyl having 3 to 7 C atoms, CF₃,NO₂, CN, OCF₃, OA, NHA, NA₂, or NH₂, R⁶ is phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-,n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or3,6-difluoro-, dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl,3,4,5-trimethoxy- or triethoxyphenyl, thiophen-2-yl or thiophen-3-yl, R³is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-,2,6-difluoro- or dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3-or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl,isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or3-pyrazinyl or 2- or 3-furanyl, R¹ denotes CO₂R⁵, (CH₂)_(n)COHet, CHO,(CH₂)_(n)OR⁵, (CH₂)_(n)Het, (CH₂)_(n)N(R⁵)₂, CH═N-OA, CH₂CH═N-OA,(CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het, (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂OR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃,(CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵, (CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂,CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar, R⁵ denotes H or A A denotesstraight-chain or branched alkyl or alkoxy having 1 to 10 C atoms, oralkenyl or alkenyloxyalkyl having 2 to 10 C atoms, Het is 1-piperidyl,1-piperazyl, 1-(4-methyl)piperazyl, 1-(4-ethyl)piperazinyl,1-(4-cyclopentyl)piperazinyl, 4-methylpiperazin-1-ylamine,1-pyrrolidinyl, 1-pyrazolidinyl 1-(2-methyl)pyrazolidinyl,1-imidazolidinyl or 1-(3-methyl)imidazolidinyl or 4-pyridyl, which isunsubstituted or substituted by one or more CN group, 2- or 4-pyridazyl,2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl, or a group of one of theformulae below

Ar denotes a phenyl radical which is unsubstituted or mono orpolysubstituted by A and/or Hal, OR⁵, OOCR⁵, COOR⁵, CON(R⁵)₂, CN, NO₂,NH₂, NHCOR⁵, CF₃ or SO₂CH₃, X denotes CH or N, n denotes 0, 1, 2, 3, 4or 5 and Hal denotes F, Cl, Br or I, where, in the case that X has themeaning CH, R² and R⁴ do not simultaneously denote H, or a salt,enantiomer, or racemate thereof, or a mixture of enantiomers.
 2. Acompound according to claim 1, in which X has the meaning N.
 3. Acompound of formula IA, IB, IC, ID, IE or IF:

in which R³ is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl,2,3-, 2,4-, 2,5-, 2,6-difluoro- or dicyanophenyl, thiophen-2-yl orthiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or5-thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or5-pyrimidyl, 2- or 3-pyrazinyl or 2- or 3-furanyl, R⁴ denote H, A, Hal,cycloalkyl having 3 to 7 C atoms, CF₃, NO₂, CN, OCF₃, OA, NHA, NA₂ orNH₂, A denotes straight-chain or branched alkyl or alkoxy having 1 to 10C atoms, or alkenyl or alkenyloxyalkyl having 2 to 10 C atoms, Haldenotes F, Cl, Br or I, X denotes CH or N, where, in the case that X hasthe meaning CH, R⁴ in the compounds of formulae IA, IC and IE does notdenote H, and R⁶ is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro-, dichloro- ordicyanophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxy- ortriethoxyphenyl, thiophen-2-yl or thiophen-3-yl.
 4. A process forpreparing a compound of claim 1, which is of formula IA

in which R³, R⁴, R⁶, X and A have the meaning indicated for the compoundof formula I or a salt thereof, comprising reacting a compound offormula II

or an acid-addition salt thereof, in which R⁴, R⁶ and X have themeanings indicated for the compound of formula I, with a compound offormula III

in which A and R³ have the meanings indicated for the compound offormula I, and/or converting a basic compound of formula IA into one ofits salts by treatment with an acid.
 5. A process for preparing acompound of formula IB

in which R³ is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-, n-propyl- or n-butylphenyl,2,3-, 2,4-, 2,5-, 2,6-difluoro- or dicyanophenyl, thiophen-2-yl orthiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or5-thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or5-pyrimidyl, 2- or 3-pyrazinyl or 2- or 3-furanyl, R⁴ denote H, A, Hal,cycloalkyl having 3 to 7 C atoms, CF₃, NO₂, CN, OCF₃, OA, NHA, NA₂ orNH₂, A denotes straight-chain or branched alkyl or alkoxy having 1 to 10C atoms, or alkenyl or alkenyloxyalkyl having 2 to 10 C atoms, Haldenotes F, Cl, Br or I, X denotes CH or N, R⁶ is phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-,n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or3,6-difluoro-, dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl,3,4,5-trimethoxy- or triethoxyphenyl, thiophen-2-yl or thiophen-3-yl, ora salt thereof, comprising reacting a compound of formula II

or an acid-addition salt thereof, in which R⁴, R⁶ and X have themeanings indicated for the compound of formula IB, with a compound offormula IV

in which A and R³ have the meanings indicated for the compound offormula IB, and/or converting a basic compound of formula IB into one ofits salts by treatment with an acid.
 6. A pharmaceutical compositioncomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts, and a pharmaceutically acceptablecarrier,

in which R², R⁴ denote H, A, Hal, cycloalkyl having 3 to 7 C atoms, CF₃,NO₂, CN, OCF₃, OA, NHA, NA₂ or NH₂, R⁶ is phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-,n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or3,6-difluoro-, dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl,3,4,5-trimethoxy- or triethoxyphenyl, thiophen-2-yl or thiophen-3-yl, R³is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-,2,6-difluoro- or dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3-or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl,isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or3-pyrazinyl or 2- or 3-furanyl, R¹ denotes H or CO₂R⁵, (CH₂)_(n)COHet,CHO, (CH₂)_(n)OR⁵, (CH₂)_(n)Het, (CH₂)₂N(R⁵)₂, CH═N-OA, CH₂CH═N-OA,(CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het, (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂OR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃,(CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵, (CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂,CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar, R⁵ denotes H or A A denotesstraight-chain or branched alkyl or alkoxy having 1 to 10 C atoms, oralkenyl or alkenyloxyalkyl having 2 to 10 C atoms, Het is 1-piperidyl,1-piperazyl, 1-(4-methyl)piperazyl, 1-(4-ethyl)piperazinyl,1-(4-cyclopentyl)piperazinyl, 4-methylpiperazin-1-ylamine,1-pyrrolidinyl, 1-pyrazolidinyl 1-(2-methyl)pyrazolidinyl,1-imidazolidinyl or 1-(3-methyl)imidazolidinyl or 4-pyridyl, which isunsubstituted or substituted by one or more CN group, 2- or 4-pyridazyl,2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl, or a group of one of theformulae below

Ar denotes a phenyl radical which is unsubstituted or mono orpolysubstituted by A and/or Hal, OR⁵, OOCR⁵, COOR⁵, CON(R⁵)₂, CN, NO₂,NH₂, NHCOR⁵, CF₃ or SO₂CH₃, X denotes CH or N, n denotes 0, 1, 2, 3, 4or 5 and Hal denotes F, Cl, Br or I, where, in the case that X has themeaning CH, R² and R⁴ do not simultaneously denote H, or a salt,enantiomer, or racemate thereof, or a mixture of enantiomers.
 7. Aprocess for the preparation of a pharmaceutical composition, comprisingcombining a compound of the formula I according to claim 6 and/or one ofits physiological acceptable salts into a suitable dosage form togetherwith at least one solid, liquid or semi-liquid excipient or adjuvant. 8.A method for the in vitro inhibition of 5-HT2A receptor, comprisingadministering to said receptor a pharmaceutical composition according toclaim
 6. 9. A compound according to claim 1, in which R¹ denotes(CH₂)_(n)COHet, CHO, (CH₂)_(n)OR⁵, (CH₂)_(n)Het, (CH₂)_(n)N(R⁵)₂,CH═N-OA, CH₂CH═N-OA, (CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het, (CH₂)_(n)CH═N-Het,(CH₂)_(n)OCOR′, (CH₂)_(n)N(R⁵)CH₂CH₂OR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃,(CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵, (CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂,CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar.
 10. A compound according to claim 1, inwhich R¹ denotes CO₂R⁵, COHet, CHO, (CH₂)_(n)OR⁵, (CH₂)_(n)Het,(CH₂)_(n)N(R⁵)₂, CH═N-OA, CH₂CH═N-OA, (CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het,(CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR′, (CH₂)_(n)N(R⁵)CH₂CH₂OR⁵,(CH₂)_(n)N(R⁵)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵,(CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′, (CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂,CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂, CH═CHCH₂OR⁵ or(CH₂)_(n)N(R⁵)Ar.
 11. A compound according to claim 1, in which R¹denotes (CH₂)_(n)Het, (CH₂)_(n)N(R⁵)₂, CH═N-OA, CH₂CH═N-OA,(CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het, (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂OR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃,(CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵, (CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂,CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar.
 12. A compound according to claim 1 ora pharmaceutically acceptable salt thereof.
 13. A compound according toclaim 1, in which R³ is thiophen-2-yl or thiophen-3-yl, 2-, 4- or5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolinyl, 2- or4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl or 2- or3-furanyl.
 14. A compound according to claim 1, in which R³ is 2- or3-furanyl.
 15. A compound according to claim 1, in which R⁴ denote A,Hal, cycloalkyl having 3 to 7 C atoms, CF₃, NO₂, CN, OCF₃, OA, NHA, NA₂,or NH₂.
 16. A compound according to claim 1, in which A denotesstraight-chain or branched alkyl or alkoxy having 3 to 10 C atoms, oralkenyl or alkenyloxyalkyl having 3 to 10 C atoms.
 17. A compound offormula I

in which R², R⁴ denote H, A, Hal, cycloalkyl having 3 to 7 C atoms, CF₃,NO₂, CN, OCF₃, OA, NHA, NA₂, or NH₂, R⁶ is phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, ethyl-,n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or3,6-difluoro-, dichloro- or dicyanophenyl, 3,4,5-trifluorophenyl,3,4,5-trimethoxy- or triethoxyphenyl, thiophen-2-yl or thiophen-3-yl, R³is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or4-methyl-, ethyl-, n-propyl- or n-butylphenyl, 2,3-, 2,4-, 2,5-,2,6-difluoro- or dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3-or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl,isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or3-pyrazinyl or 2- or 3-furanyl, R¹ denotes H or CO₂R⁵, (CH₂)_(n)COHet,CHO, (CH₂)_(n)OR⁵, (CH₂)_(n)Het, (CH₂)_(n)N(R⁵)₂, CH═N-OA, CH₂CH═N-OA,(CH₂)_(n)NHOA, (CH₂)_(n)(R⁵)Het, (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂OR⁵, (CH₂)_(n)N(R⁵)CH₂CH₂OCF₃,(CH₂)_(n)N(R⁵)C(R⁵)OCOR⁵, (CH₂)_(n)N(R′)CH₂COHet, (CH₂)_(n)N(R⁵)CH₂Het,(CH₂)_(n)N(R⁵)CH₂CH₂Het, (CH₂)_(n)N(R⁵)CH₂CH₂N(R′)CH₂OCOR′,(CH₂)_(n)N(R⁵)CH₂CH₂N(R⁵)₂, CH═CHCOOR⁵, CH═CHCH₂NR⁵Het, CH═CHCH₂N(R⁵)₂,CH═CHCH₂OR⁵ or (CH₂)_(n)N(R⁵)Ar, R⁵ denotes H or A A denotesstraight-chain or branched alkyl or alkoxy having 1 to 10 C atoms, oralkenyl or alkenyloxyalkyl having 2 to 10 C atoms, Het is 1-piperidyl,1-piperazyl, 1-(4-methyl)piperazyl, 1-(4-ethyl)piperazinyl,1-(4-cyclopentyl)piperazinyl, 4-methylpiperazin-1-ylamine,1-pyrrolidinyl, 1-pyrazolidinyl 1-(2-methyl)pyrazolidinyl,1-imidazolidinyl or 1-(3-methyl)imidazolidinyl or 4-pyridyl, which isunsubstituted or substituted by one or more CN group, 2- or 4-pyridazyl,2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl, or a group of one of theformulae below

Ar denotes a phenyl radical which is unsubstituted or mono orpolysubstituted by A and/or Hal, OR⁵, OOCR⁵, COOR⁵, CON(R⁵)₂, CN, NO₂,NH₂, NHCOR⁵, CF₃ or SO₂CH₃, X denotes CH or N, n denotes 0, 1, 2, 3, 4or 5 and Hal denotes F, Cl, Br or I, where, in the case that X has themeaning CH, R² and R⁴ do not simultaneously denote H, or a salt,enantiomer, or racemate thereof, or a mixture of enantiomers, wherein atleast one of the following three conditions I, II, or III is satisfied:I) R⁴ denotes H, Hal, CN, A or NO₂; II) R² denotes H or alkyl; III) Hetis


18. A compound according to claim 17, in which R⁴ denotes H, Hal, CN, Aor NO₂.
 19. A compound according to claim 17, in which R² denotes H oralkyl.
 20. A compound according to claim 17, in which Het is